ArticleBlood advances2022
Neutrophil cathepsin G proteolysis of protease-activated receptor 4 generates a novel, functional tethered ligand.
Article in Blood advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Differential regulation of cyclic adenosine monophosphate by phosphodiesterase 3A discriminates thrombin-induced protease activated receptor 1- and 4-dependent platelet activation.Journal of thrombosis and haemostasis : JTH · 2026Article
- Neutrophil cathepsin G potentiates biased signaling through protease-activated receptor 4.Blood advances · 2026Article
- It's a Trap!-Potential of Cathepsins in NET Formation.International journal of molecular sciences · 2025Review
- From theory to platelets: unraveling the history and complexities of biased signaling.Blood vessels, thrombosis & hemostasis · 2025Review
- Dengue virus infection: how platelet-leukocyte crosstalk shapes thrombotic events and inflammation.Molecular biology reports · 2025Review
- The multifaceted roles of cathepsins in immune and inflammatory responses: implications for cancer therapy, autoimmune diseases, and infectious diseases.Biomarker research · 2024Review
- Elevated protease-activated receptor 4 (PAR4) gene expression in Alzheimer's disease predicts cognitive decline.Neurobiology of aging · 2024Article
- Cathepsin K-Activated Probe for Fluoro-Photoacoustic Imaging of Early Osteolytic Metastasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Species Differences in Platelet Protease-Activated Receptors.International journal of molecular sciences · 2023Review
- Platelet-neutrophil interaction in COVID-19 and vaccine-induced thrombotic thrombocytopenia.Frontiers in immunology · 2023Review
- Neutrophil-Platelet Interactions as Novel Treatment Targets in Cardiovascular Disease.Frontiers in cardiovascular medicine · 2021Review
- C1-inhibitor influence on platelet activation by thrombin receptors agonists.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/HemostasisArticle
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Platelet-neutrophil interactions regulate ischemic vascular injury. Platelets are activated by serine proteases that cleave protease-activated receptor (PAR) amino termini, resulting in an activating tethered ligand. Neutrophils release cathepsin G (CatG) at sites of injury and inflammation, which activates PAR4 but not PAR1, although the molecular mechanism of CatG-induced PAR4 activation is unknown. We show that blockade of the canonical PAR4 thrombin cleavage site did not alter CatG-induced platelet aggregation, suggesting CatG cleaves a different site than thrombin. Mass spectrometry analysis using PAR4 N-terminus peptides revealed CatG cleavage at Ser67-Arg68. A synthetic peptide, RALLLGWVPTR, representing the tethered ligand resulting from CatG proteolyzed PAR4, induced PAR4-dependent calcium flux and greater platelet aggregation than the thrombin-generated GYPGQV peptide. Mutating PAR4 Ser67or Arg68 reduced CatG-induced calcium flux without affecting thrombin-induced calcium flux. Dog platelets, which contain a conserved CatG PAR4 Ser-Arg cleavage site, aggregated in response to human CatG and RALLLGWVPTR, while mouse (Ser-Gln) and rat (Ser-Glu) platelets were unresponsive. Thus, CatG amputates the PAR4 thrombin cleavage site by cleavage at Ser67-Arg68 and activates PAR4 by generating a new functional tethered ligand. These findings support PAR4 as an important CatG signaling receptor and suggest a novel therapeutic approach for blocking platelet-neutrophil-mediated pathophysiologies.
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Registered trials
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